Bleeding disorders, and particularly congenital or acquired deficiencies in coagulation factors, are typically treated by factor replacement. Congenital coagulation disorders include hemophilia, a recessive X-linked disorder involving a deficiency of coagulation factor VIII (hemophilia A) or factor IX (hemophilia B), and von Willebrand's disease, a rare bleeding disorder involving a severe deficiency of von Willebrand factor. Hemophilia C is a milder form of hemophilia caused by a deficiency in factor XI. It is usually asymptomatic, but factor replacement therapy may be required during surgery. Acquired coagulation disorders may arise in individuals without a previous history of bleeding as a result of a disease process. For example, acquired coagulation disorders may be caused by inhibitors or autoimmunity against blood coagulation factors, such as factor VIII, von Willebrand factor, factors IX, V, XI, XII and XIII; or by hemostatic disorders such as caused by liver disease, which may be associated with decreased synthesis of coagulation factors. As many as 20% of patients receiving chronic factor replacement therapy may generate neutralizing antibodies to replacement factors. Protein therapeutics are produced by recombinant technology or are prepared from plasma and can only be administered intravenously, which is inconvenient. Conventional therapy for hemophilia A and factor VIII inhibitor patients is accomplished by therapeutics like recombinant factor VIII or procoagulant bypassing agents, for example FEIBA or recombinant factor VIIa. Although effective, development of inhibitory antibodies which render the therapy ineffective is a common occurrence. FVIIa and FEIBA as therapeutics for the treatment of FVIII inhibitor patients have quite short half lives and so require frequent intravenous administration.
Naito and Fujikawa (1991) J Biol Chem 266: 7353-7358 and Gailani and Broze Jr (1993) Blood 82: 813-819 both disclose that negatively charged surfaces such as dextran sulfate, sulfatide or, heparin can facilitate the activation of Factor XI by thrombin or Factor XIa in vitro. However, such materials would not have been considered suitable for therapy of blood coagulation disorders. Typical dextran sulfate and heparin compounds have anticoagulant effects in vivo. Furthermore, these agents would activate contact activation factors (Factor XII, high molecular weight kininogen or prekallikrein) in vivo, which could be dangerous. Localized contact activation on platelets was suggested to be of physiologic relevance (Smith S A and Morrissey J H, Thromb Haemost. 2008 Jul. 26. [Epub ahead of print]). Systemic contact activation might lead to a systemic increase in the level of bradykinin which is generated by the cleavage of HMWK by kallikrein-like enzymes. Unregulated bradykinin release might increase vascular permeability, vascular leakage and possibly edema formation. Such a clinical phenotype is known from the disease hereditary angioedema which is characterised by a functional deficiency in the FXIIa inhibitor C1-Inhibitor.
There is a need for non-protein therapeutics for treating bleeding disorders, which are safe, convenient and effective.
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